Although the etiology of many psychiatric disorders remains largely unknown, it is accepted that the underlying causes of these pathologies involve multiple genetic and environmental factors. The marked gender bias in the prevalence of most of these conditions suggests that mechanisms of brain sexual differentiation and/or sex steroid action in the brain might be contributing to their pathophysiology. Thyroid hormones (TH) are known to exert profound effects in the developing brain as well as to antagonize in this tissue the action of estrogen (E) in the regulation of gene expression and behavior. Robust homeostatic mechanisms are in place to ensure that TH concentrations are appropriate for a particular brain region at a specific developmental stage. One of these mechanisms is the type 3 deiodinase (D3), an enzyme that degrades TH. D3 is highly expressed in the developing and adult brain and is encoded by an imprinted gene. Preliminary results in D3-deficient mice generated in our laboratory indicate that D3 is necessary for adequate TH status and TH-dependent gene expression in most brain regions, including the hypothalamus. The lack of an active D3 also results in alterations in brain structure, abnormal social behavior and decreased levels of certain neuropeptides related to behavioral functions. The goal of the present Exploratory and developmental Research Grant (R21) application is to determine the role of the type 3 deiodinase (D3) in the sexual differentiation of the brain and/or in sex steroid action in this tissue. Using D3-deficient mice, I propose i) To define the regulatory functions of D3 and TH in various paradigms of E action in the developing and adult brain;and ii) To determine the effect of D3 deficiency on the E-dependent regulation and sexual dimorphism of selected neuropeptides related to behavior. These initial studies may identify D3 as a novel factor involved in the sexual differentiation of the brain and may point to altered TH metabolism and action in the brain as an important process influencing brain development and function and determining adult behavior. These studies may open a new area of research into the mechanisms contributing to the neurobiology of neurological disorders. As these findings may apply to humans, this and future studies may provide novel targets for therapeutic interventions aimed at preventing and treating developmental and psychiatric disorders. PUBLIC HEALTH RELEVANCE: The studies proposed will use normal mice and mice deficient in the type 3 deiodinase to determine whether this enzyme has a role in regulating sex steroid action in the developing and/or adult brain and therefore affects brain sexual differentiation and the generation of sexually dimorphic features in the central nervous system. The confirmation of this hypothesis will provide a novel mechanism that may shed some light into the etiology and pathophysiology of certain neurological conditions in humans that exhibit a gender bias and that are characterized by abnormal behavior, such as autism, schizophrenia, bipolar disorder, depression and others.